tbuckley/cabot-search huggingface dataset:
Patient-derived lymphoma spheroids integrating immune tumor microenvironment as preclinical follicular lymphoma models for personalized medicine
Authors: Carla Faria, Fabien Gava, Pauline Gravelle, Juan Garcia Valero, Celia Dobaño-López, Nathalie Van Acker, Cathy Quelen, Gael Jalowicki, Renaud Morin, Cédric Rossi, Jean-Michel Lagarde, Jean-Jacques Fournié, Loïc Ysebaert, Camille Laurent, Patricia Pérez-Galán, Christine Bezombes
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Follicular lymphoma (FL), the most common indolent non-Hodgkin’s Lymphoma, is a heterogeneous disease and a paradigm of the contribution of immune tumor microenvironment to disease onset, progression, and therapy resistance. Patient-derived models are scarce and fail to reproduce immune phenotypes and therapeutic responses. Methods To capture disease heterogeneity and microenvironment cues, we developed a patient-derived lymphoma spheroid (FL-PDLS) model culturing FL cells from lymph nodes (LN) with an optimized cytokine cocktail that mimics LN stimuli and maintains tumor cell viability. Results FL-PDLS, mainly composed of tumor B cells (60% on average) and autologous T cells (13% CD4 and 3% CD8 on average, respectively), rapidly organizes into patient-specific three-dimensional (3D) structures of three different morphotypes according to 3D imaging analysis. RNAseq analysis indicates that FL-PDLS reproduces FL hallmarks with the overexpression of cell cycle, BCR, or mTOR signaling related gene sets. FL-PDLS also recapitulates the exhausted immune phenotype typical of FL-LN, including expression of BTLA, TIGIT, PD-1, TIM-3, CD39 and CD73 on CD3 + T cells. These features render FL-PDLS an amenable system for immunotherapy testing. With this aim, we demonstrate that the combination of obinutuzumab (anti-CD20) and nivolumab (anti-PD1) reduces tumor load in a significant proportion of FL-PDLS. Interestingly, B cell depletion inversely correlates with the percentage of CD8 + cells positive for PD-1 and TIM-3. Conclusions In summary, FL-PDLS is a robust patient-derived 3D system that can be used as a tool to mimic FL pathology and to test novel immunotherapeutic approaches in a context of personalized medicine.
Landscape of enhancer disruption and functional screen in melanoma cells
Authors: Zhao Wang, Menghan Luo, Qian Liang, Ke Zhao, Yuelin Hu, Wei Wang, Xiangling Feng, Bolang Hu, Jianjin Teng, Tianyi You, Ran Li, Zhengkai Bao, Wenhao Pan, Tielong Yang, Chao Zhang, Ting Li, Xiaobao Dong, Xianfu Yi, Ben Liu, Li Zhao, Miaoxin Li, Kexin Chen, Weihong Song, Jilong Yang, Mulin Jun Li
Journal: Genome biology (2023)

The high mutation rate throughout the entire melanoma genome presents a major challenge in stratifying true driver events from the background mutations. Numerous recurrent non-coding alterations, such as those in enhancers, can shape tumor evolution, thereby emphasizing the importance in systematically deciphering enhancer disruptions in melanoma.
Prevalence of multiple long-term conditions (multimorbidity) in England: a whole population study of over 60 million people
Authors: Jonathan Valabhji, Emma Barron, Adrian Pratt, Nasrin Hafezparast, Rupert Dunbar-Rees, Ellie Bragan Turner, Kate Roberts, Jacqueline Mathews, Robbie Deegan, Victoria Cornelius, Jason Pickles, Gary Wainman, Chirag Bakhai, Desmond G Johnston, Edward W Gregg, Kamlesh Khunti
Journal: Journal of the Royal Society of Medicine (2023)

Objectives To determine the prevalence of multiple long-term conditions (MLTC) at whole English population level, stratifying by age, sex, socioeconomic status and ethnicity. Design A whole population study. Setting Individuals registered with a general practice in England and alive on 31 March 2020. Participants 60,004,883 individuals. Main outcome measures MLTC prevalence, defined as two or more of 35 conditions derived from a number of national patient-level datasets. Multivariable logistic regression was used to assess the independent associations of age, sex, ethnicity and deprivation decile with odds of MLTC. Results The overall prevalence of MLTC was 14.8% (8,878,231), varying from 0.9% (125,159) in those aged 0–19 years to 68.2% (1,905,979) in those aged 80 years and over. In multivariable regression analyses, compared with the 50–59 reference group, the odds ratio was 0.04 (95% confidence interval (CI): 0.04–0.04; p &lt; 0.001) for those aged 0–19 years and 10.21 (10.18–10.24; p &lt; 0.001) for those aged 80 years and over. Odds were higher for men compared with women, 1.02 (1.02–1.02; p &lt; 0.001), for the most deprived decile compared with the least deprived, 2.26 (2.25–2.27; p &lt; 0.001), and for Asian ethnicity compared with those of white ethnicity, 1.05 (1.04–1.05; p &lt; 0.001). Odds were lower for black, mixed and other ethnicities (0.94 (0.94–0.95) p &lt; 0.001, 0.87 (0.87–0.88) p &lt; 0.001 and 0.57 (0.56–0.57) p &lt; 0.001, respectively). MLTC for persons aged 0–19 years were dominated by asthma, autism and epilepsy, for persons aged 20–49 years by depression and asthma, for persons aged 50–59 years by hypertension and depression and for those aged 60 years and older, by cardiometabolic factors and osteoarthritis. There were large numbers of combinations of conditions in each age group ranging from 5936 in those aged 0–19 years to 205,534 in those aged 80 years and over. Conclusions While this study provides useful insight into the burden across the English population to assist health service delivery planning, the heterogeneity of MLTC presents challenges for delivery optimisation.
Interpregnancy Interval After Clinical Pregnancy Loss and Outcomes of the Next Frozen Embryo Transfer
Authors: Ze Wang, Yueru Meng, Xue Shang, Lu Suo, Dingying Zhao, Xinwei Han, Min Yang, Mengfei Yin, Haozhe Miao, Yixuan Wang, Huiming Yang, Yunhai Yu, Daimin Wei, Zi-Jiang Chen
Journal: JAMA Network Open (2023)

Importance The optimal interpregnancy interval (IPI) after a clinical pregnancy loss (CPL) remains controversial. Few studies have addressed the role of the IPI after a preceding CPL during in vitro fertilization (IVF) treatment. Objective To evaluate the association between different IPI lengths after a preceding CPL and pregnancy outcomes of the next frozen embryo transfer (FET). Design, Setting, and Participants This retrospective cohort study was conducted using data from the Center for Reproductive Medicine of Shandong University in China. The study included women who underwent frozen-thawed blastocyst transfer between July 1, 2017, and June 30, 2022, within 1 year after a preceding CPL during IVF treatment. Follow-up for pregnancy outcomes was completed for all participants on March 31, 2023. Data analysis was performed from April to May 2023. Exposures Interpregnancy interval length was classified as less than 3 months, 3 to less than 6 months, or 6 to 12 months. Main Outcomes and Measures Outcomes included live birth, conception, clinical pregnancy, pregnancy loss, preterm birth, small or large for gestational age, and low birth weight. Multivariable logistic regression analysis was conducted to evaluate the association between IPI and pregnancy outcomes by adjusted odds ratios (AORs). Results This study included 2433 women (mean [SD] age, 31.8 [4.6] years) who received IVF treatment. There were 338 women (13.9%) with an IPI of less than 3 months, 1347 (55.4%) with an IPI of 3 to less than 6 months, and 748 (30.7%) with an IPI of 6 to 12 months. The median (IQR) IPI lengths for the 3 groups were 77 (65-85), 128 (109-152), and 234 (202-288) days, respectively. Compared with an IPI of 6 to 12 months, shorter IPIs (&amp;amp;lt;3 and 3 to &amp;amp;lt;6 months) were associated with decreased odds of clinical pregnancy (AOR, 0.70 [95% CI, 0.53-0.92] and 0.79 [0.65-0.95]), live birth (AOR, 0.64 [95% CI, 0.48-0.85] and 0.74 [0.61-0.90]), and healthy live birth (AOR, 0.63 [95% CI, 0.46-0.87] and 0.79 [0.64-0.98]). Compared with women with an IPI of 6 to 12 months, women with shorter IPIs (&amp;amp;lt;3 and 3 to &amp;amp;lt;6 months) had a higher risk of total pregnancy loss (AOR, 1.87 [95% CI, 1.31-2.67] and 1.29 [1.00-1.66], respectively). Conclusions and Relevance The results of this study suggest that delaying the next FET for at least 6 months after a preceding CPL was associated with beneficial pregnancy outcomes, considering that a decreased likelihood of achieving clinical pregnancy and live birth was observed among women with shorter IPIs. Further prospective studies are needed to confirm these findings.
Overall Survival After Treatment Failure Among Patients With Rectal Cancer
Authors: Markus Diefenhardt, Daniel Martin, Maximilian Fleischmann, Ralf-Dieter Hofheinz, Michael Ghadimi, Claus Rödel, Emmanouil Fokas
Journal: JAMA Network Open (2023)

Oncologic outcomes among patients with rectal cancer after developing local recurrence and/or distant metastases remain poorly studied.
Imetelstat-mediated alterations in fatty acid metabolism to induce ferroptosis as a therapeutic strategy for acute myeloid leukemia
Authors: Claudia Bruedigam, Amy H. Porter, Axia Song, Gerjanne Vroeg in de Wei, Thomas Stoll, Jasmin Straube, Leanne Cooper, Guidan Cheng, Vivian F. S. Kahl, Alexander P. Sobinoff, Victoria Y. Ling, Billy Michael Chelliah Jebaraj, Yashaswini Janardhanan, Rohit Haldar, Laura J. Bray, Lars Bullinger, Florian H. Heidel, Glen A. Kennedy, Michelle M. Hill, Hilda A. Pickett, Omar Abdel-Wahab, Gunter Hartel, Steven W. Lane
Journal: Nature Cancer (2023)

Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant NRAS and oxidative stress-associated gene expression signatures. Unbiased, genome-wide CRISPR/Cas9 editing identifies ferroptosis regulators as key mediators of imetelstat efficacy. Imetelstat promotes the formation of polyunsaturated fatty acid-containing phospholipids, causing excessive levels of lipid peroxidation and oxidative stress. Pharmacological inhibition of ferroptosis diminishes imetelstat efficacy. We leverage these mechanistic insights to develop an optimized therapeutic strategy using oxidative stress-inducing chemotherapy to sensitize patient samples to imetelstat causing substantial disease control in AML.
Smoking exposure trajectories and pulmonary function in early adulthood in a Brazilian cohort
Authors: P. Weber, A.M.B. Menezes, H. Gonçalves, P.D. de Oliveira, A. Wendt, R. Perez-Padilla, F.C. Wehrmeister
Journal: Pulmonology (2023)

To investigate smoking trajectories and their association with pulmonary function (PF) and respiratory symptoms at age 22. Data from a population-based cohort study of 3350 individuals and their spirometries were analysed. The outcomes were: forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), forced expiratory flow at the mid expiratory phase (FEF25–75 %), FEV1/FVC and FEF25–75/FVC ratio. Smoking data were collected at perinatal follow-up (gestational exposure) and 15, 18 and 22 years. Group-based trajectory model was applied. Four groups were identified: no exposure (NE), gestational (GE), gestational and adulthood (GAE) and continuous (CE) exposure. Both CE and GAE trajectories were associated with lower values of FEV1/FVC (−1.77pp; p = 0.01 and −1.58 pp; p<0.001 respectively) and FEF25–75/FVC ratio (−7.27pp; p = 0.019 and −6.04pp; p<0.001 respectively) compared to the NE trajectory. Lower FEV1 and FEF25–75 % values were also related to the GAE trajectory (−68 ml; p = 0.03 and −253 ml/s; p<0.001 respectively). Compared to those who never smoked, individuals who smoked 10 or more cigarettes daily presented a reduction in the FEV1/FVC ratio by 1.37pp (p<0.001), FEF25–75 % by 126 ml (p = 0.012) and FEF25–75 %/FVC ratio by 3.62pp (p = 0.011). CE trajectory showed higher odds of wheezing (OR 4.14; p<0.001) and cough (OR 2.39; p = 0.002) compared to the non-exposed group. The in-uterus exposure to maternal smoking reduces PF later in life. However, the perpetuation of smoking behaviour throughout adolescence and early adulthood is determinant for PF main reduction and the emergence of respiratory-related symptoms.
Multiplex imaging in immuno-oncology
Authors: Chen Zhao, Ronald N Germain
Journal: Journal for ImmunoTherapy of Cancer (2023)

Multiplex imaging has emerged as an invaluable tool for immune-oncologists and translational researchers, enabling them to examine intricate interactions among immune cells, stroma, matrix, and malignant cells within the tumor microenvironment (TME). It holds significant promise in the quest to discover improved biomarkers for treatment stratification and identify novel therapeutic targets. Nonetheless, several challenges exist in the realms of study design, experiment optimization, and data analysis. In this review, our aim is to present an overview of the utilization of multiplex imaging in immuno-oncology studies and inform novice researchers about the fundamental principles at each stage of the imaging and analysis process.
Early changes in renal function during rapid up‐titration of guideline‐directed medical therapy following an admission for acute heart failure
Authors: Jozine M. ter Maaten, Alexandre Mebazaa, Beth Davison, Christopher Edwards, Marianna Adamo, Mattia Arrigo, Marianela Barros, Jan Biegus, Jelena Čelutkienė, Kamilė Čerlinskaitė‐Bajorė, Ovidiu Chioncel, Alain Cohen‐Solal, Albertino Damasceno, Rafael Diaz, Gerasimos Filippatos, Etienne Gayat, Antoine Kimmoun, Carolyn S.P. Lam, Valentine Leopold, Maria Novosadova, Matteo Pagnesi, Peter S. Pang, Piotr Ponikowski, Hadiza Saidu, Karen Sliwa, Koji Takagi, Daniela Tomasoni, Marco Metra, Gad Cotter, Adriaan A. Voors
Journal: European Journal of Heart Failure (2023)

Aim In this subgroup analysis of STRONG‐HF, we explored the association between changes in renal function and efficacy of rapid up‐titration of guideline‐directed medical therapy (GDMT) according to a high‐intensity care (HIC) strategy. Methods and results In patients randomized to the HIC arm ( n = 542), renal function was assessed at baseline and during follow‐up visits. We studied the association with clinical characteristics and outcomes of a decrease in estimated glomerular filtration rate (eGFR) at week 1, defined as ≥15% decrease from baseline. Patients in the usual care group ( n = 536) were seen at day 90. The treatment effect of HIC versus usual care was independent of baseline eGFR ( p ‐interaction = 0.4809). A decrease in eGFR within 1 week occurred in 77 (15.5%) patients and was associated with more rales on examination ( p = 0.004), and a higher New York Heart Association class at the corresponding visit. Following the decrease in eGFR at 1 week, lower average optimal doses of GDMT were prescribed during follow‐up ( p = 0.0210) and smaller reductions in N‐terminal pro‐B‐type natriuretic peptide occurred (geometrical mean 0.81 in no eGFR decrease vs 1.12 in GFR decrease, p = 0.0003). The rate of heart failure (HF) readmission or death at 180 days was 12.3% in no eGFR decrease versus 18.5% in eGFR decrease ( p = 0.2274) and HF readmissions were 7.8% versus 16.6% ( p = 0.0496). Conclusions In the STRONG‐HF study, HIC reduced 180‐day HF readmission or death regardless of baseline eGFR. An early decrease in eGFR during rapid up‐titration of GDMT was associated with more evidence of congestion, yet lower doses of GDMT during follow‐up.
Reduced Mitochondrial Protein Translation Promotes Cardiomyocyte Proliferation and Heart Regeneration
Authors: Feng Gao, Tian Liang, Yao Wei Lu, Linbin Pu, Xuyang Fu, Xiaoxuan Dong, Tingting Hong, Feng Zhang, Ning Liu, Yuxia Zhou, Hongkun Wang, Ping Liang, Yuxuan Guo, Hong Yu, Wei Zhu, Xinyang Hu, Hong Chen, Bin Zhou, William T. Pu, John D. Mably, Jian’an Wang, Da-Zhi Wang, Jinghai Chen
Journal: Circulation (2023)

The importance of mitochondria in normal heart function are well recognized and recent studies have implicated changes in mitochondrial metabolism with some forms of heart disease. Previous studies demonstrated that knockdown of the mitochondrial ribosomal protein S5 (MRPS5) by small interfering RNA (siRNA) inhibits mitochondrial translation and thereby causes a mitonuclear protein imbalance. Therefore, we decided to examine the effects of MRPS5 loss and the role of these processes on cardiomyocyte proliferation.
Segmented filamentous bacteria–induced epithelial MHCII regulates cognate CD4+ IELs and epithelial turnover
Authors: Tomáš Brabec, Martin Schwarzer, Katarína Kováčová, Martina Dobešová, Dagmar Schierová, Jiří Březina, Iva Pacáková, Dagmar Šrůtková, Osher Ben-Nun, Yael Goldfarb, Iva Šplíchalová, Michal Kolář, Jakub Abramson, Dominik Filipp, Jan Dobeš
Journal: The Journal of Experimental Medicine (2023)

Intestinal epithelial cells have the capacity to upregulate MHCII molecules in response to certain epithelial-adhesive microbes, such as segmented filamentous bacteria (SFB). However, the mechanism regulating MHCII expression as well as the impact of epithelial MHCII-mediated antigen presentation on T cell responses targeting those microbes remains elusive. Here, we identify the cellular network that regulates MHCII expression on the intestinal epithelium in response to SFB. Since MHCII on the intestinal epithelium is dispensable for SFB-induced Th17 response, we explored other CD4+ T cell-based responses induced by SFB. We found that SFB drive the conversion of cognate CD4+ T cells to granzyme+ CD8α+ intraepithelial lymphocytes. These cells accumulate in small intestinal intraepithelial space in response to SFB. Yet, their accumulation is abrogated by the ablation of MHCII on the intestinal epithelium. Finally, we show that this mechanism is indispensable for the SFB-driven increase in the turnover of epithelial cells in the ileum. This study identifies a previously uncharacterized immune response to SFB, which is dependent on the epithelial MHCII function.
Current perspectives on mass spectrometry-based immunopeptidomics: the computational angle to tumor antigen discovery
Authors: Bing Zhang, Michal Bassani-Sternberg
Journal: Journal for ImmunoTherapy of Cancer (2023)

Identification of tumor antigens presented by the human leucocyte antigen (HLA) molecules is essential for the design of effective and safe cancer immunotherapies that rely on T cell recognition and killing of tumor cells. Mass spectrometry (MS)-based immunopeptidomics enables high-throughput, direct identification of HLA-bound peptides from a variety of cell lines, tumor tissues, and healthy tissues. It involves immunoaffinity purification of HLA complexes followed by MS profiling of the extracted peptides using data-dependent acquisition, data-independent acquisition, or targeted approaches. By incorporating DNA, RNA, and ribosome sequencing data into immunopeptidomics data analysis, the proteogenomic approach provides a powerful means for identifying tumor antigens encoded within the canonical open reading frames of annotated coding genes and non-canonical tumor antigens derived from presumably non-coding regions of our genome. We discuss emerging computational challenges in immunopeptidomics data analysis and tumor antigen identification, highlighting key considerations in the proteogenomics-based approach, including accurate DNA, RNA and ribosomal sequencing data analysis, careful incorporation of predicted novel protein sequences into reference protein database, special quality control in MS data analysis due to the expanded and heterogeneous search space, cancer-specificity determination, and immunogenicity prediction. The advancements in technology and computation is continually enabling us to identify tumor antigens with higher sensitivity and accuracy, paving the way toward the development of more effective cancer immunotherapies.
Long‐term outcome after upgrade to cardiac resynchronization therapy: A propensity score‐matched analysis
Authors: Sander Trenson, Gabor Voros, Pieter Martens, Sebastian Ingelaere, Pascal Betschart, Jens‐Uwe Voigt, Matthias Dupont, Alexander Breitenstein, Jan Steffel, Rik Willems, Frank Ruschitzka, Wilfried Mullens, Stephan Winnik, Bert Vandenberk
Journal: European Journal of Heart Failure (2023)
Alterations in Cancer Treatment During the First Year of the COVID-19 Pandemic in the US
Authors: Lauren M. Janczewski, Joseph Cotler, Ryan P. Merkow, Bryan Palis, Heidi Nelson, Timothy Mullett, Daniel J. Boffa
Journal: JAMA Network Open (2023)

Importance The COVID-19 pandemic created challenges to the evaluation and treatment of cancer, and abrupt resource diversion toward patients with COVID-19 put cancer treatment on hold for many patients. Previous reports have shown substantial declines in cancer screening and diagnoses in 2020; however, the extent to which the delivery of cancer care was altered remains unclear. Objective To assess alterations in cancer treatment in the US during the first year of the COVID-19 pandemic. Design, Setting, and Participants This retrospective cohort study used data from the National Cancer Database (NCDB) on patients older than 18 years with newly diagnosed cancer from January 1, 2018, to December 31, 2020. Main Outcomes and Measures The main outcomes were accessibility (time to treatment, travel distance, and multi-institutional care), availability (proportional changes in cancer treatment between years), and utilization (reductions by treatment modality, hospital type) of cancer treatment in 2020 compared with 2018 to 2019. Autoregressive models forecasted expected findings for 2020 based on observations from prior years. Results Of 1 229 654 patients identified in the NCDB in 2020, 1 074 225 were treated for cancer, representing a 16.8% reduction from what was expected. Patients were predominately female (53.8%), with a median age of 66 years (IQR, 57-74 years), similar to demographics in 2018 and 2019. Median time between diagnosis and treatment was 26 days (IQR, 0-36 days) in 2020, and median travel distance for care was 11.1 miles (IQR, 5.0-25.3 miles), similar to 2018 and 2019. In 2020, fewer patients traveled longer distances (20.2% reduction of patients traveling &amp;amp;gt;35 miles). The proportions of patients treated with chemotherapy (32.0%), radiation (29.5%), and surgery (57.1%) were similar to those in 2018 and 2019. Overall, 146 805 fewer patients than expected underwent surgery, 80 480 fewer received radiation, and 68 014 fewer received chemotherapy. Academic hospitals experienced the greatest reduction in cancer surgery and treatment, with a decrease of approximately 484 patients (−19.0%) per hospital compared with 99 patients (−12.6%) at community hospitals and 110 patients (−12.8%) at integrated networks. Conclusions and Relevance This study found that among patients diagnosed with cancer in 2020, access and availability of treatment remained intact; however, reductions in treated patients varied across treatment modalities and were greater at academic hospitals than at community hospitals and integrated networks compared with expected values. These results suggest the resilience of cancer service lines and frame the economic losses from reductions in cancer treatment during the pandemic.